Combined Analyses of Circulating Tumor DNA and Immunoscore in Patients With Stage III Colon Cancer: A Post Hoc Analysis of the PRODIGE-GERCOR IDEA-France/HORG-IDEA-Greece Trials

Abstract

Purpose: Immunoscore (IS) and circulating tumor DNA (ctDNA) are two emerging technologies in improving prognostication and tailoring adjuvant treatments in patients resected from a stage III colon cancer (CC). Here, we analyzed the prognostic value of the two biomarkers in patients who participated in the randomized phase III IDEA-France and HORG trials.

Methods: Plasma samples were collected after surgery and before adjuvant chemotherapy. ctDNA analysis was performed using a clinically validated, personalized, tumor-informed 16-plex protein chain reaction assay. Multivariable analyses for time to recurrence (TTR; patients without recurrence or death due to CC) and overall survival (OS) were performed using ctDNA and IS results, along with other parameters including treatment duration and disease risk group.

Results: Of the 554 patients with available ctDNA results, 445 were ctDNA-negative (80.3%) and 109 were ctDNA-positive (19.7%); baseline characteristics showed more T4/N2 and venous embolism/lymphatic invasion/perineural invasion+ in ctDNA-positive patients. With a median follow-up of 6.7 years, the 2-year TTR rate was 43.5% (95% CI, 34.1 to 52.6) for ctDNA-positive patients and 88.1% (95% CI, 84.7 to 90.8) for ctDNA-negative patients (P < .0001). ctDNA was confirmed as an independent prognostic marker for both TTR (adjusted hazard ratio [adjHR], 5.21 [95% CI, 3.59 to 7.58]; P < .001) and OS (adjHR, 4.84 [95% CI, 3.40 to 6.89]; P < .001). ctDNA remained the most significant prognostic factor irrespective of disease stage, treatment duration, and IS results. IS was not prognostic in ctDNA-positive patients but remained a significant prognostic tool for ctDNA-negative patients.

Conclusion: In this combined analysis of two adjuvant trials dedicated to patients with stage III CC after surgery, ctDNA was detectable in 19.7% of the patients and was confirmed as a major independent prognostic biomarker. IS seems to bring additional prognostic information in the 80.3% of patients who are ctDNA-negative.

Trial registration: ClinicalTrials.gov NCT00958737 NCT01308066.

FIG 1.

Flowchart. ctDNA, circulating tumor DNA; int, intermediate; IS, Immunoscore; mITT, modified intention-to-treat population.

FIG 2.

Kaplan-Meier estimate of (A) TTR in ctDNA-positive and ctDNA-negative patients and (B) OS in ctDNA-positive and ctDNA-negative patients. ctDNA, circulating tumor DNA; HR, hazard ratio; KM Est, Kaplan-Meier estimates; OS, overall survival; TTR, time to recurrence.

FIG 3.

Kaplan-Meier estimate of TTR according to (A) ctDNA status and treatment duration (3 v 6 months; A) and (B) risk group (T1-3/N1 v T4 and/or N2; B), and (C) Immunoscore classification (low v intermediate v high; C). CT, computed tomography; ctDNA, circulating tumor DNA; HR, hazard ratio; IS, Immunoscore; TN, tumor and node; TTR, time to recurrence.

FIG A1.

Kaplan-Meier estimates of TTR from random assignment according to ctDNA information available or not. ctDNA, circulating tumor DNA; HR, hazard ratio; TTR, time to recurrence.

FIG A2.

Kaplan-Meier estimates of TTR from random assignment according to treatment duration in (A) the mITT population (n = 2,717) and (B) patients with ctDNA available (n = 554). ctDNA, circulating tumor DNA; HR, hazard ratio; KM Est, Kaplan-Meier estimates; mITT, modified intention-to-treat population; TTR, time to recurrence.

FIG A3.

Kaplan-Meier estimates of OS from random assignment according to ctDNA and (A) treatment duration or (B) disease stage. CT, computed tomography; ctDNA, circulating tumor DNA; HR, hazard ratio; OS, overall survival; TN, tumor and node.

FIG A4.

Kaplan-Meier estimates of TTR from random assignment according to treatment duration, disease stage, and ctDNA status. CT, computed tomography; ctDNA, circulating tumor DNA; KM Est, Kaplan-Meier estimates; TN, tumor and node; TTR, time to recurrence.